Many patient and injury characteristics impair the biology of bone regeneration and lead to delayed clinical fracture healing. This is a relatively common problem, occurring in non-unions, spinal fusion failures, and in elderly patients, among other clinical situations, all of which lead to substantial patient morbidity and societal burden. Fracture healing normally occurs by a series of complex molecular events. The hedgehog molecular pathway is directly related to bone formation and bone healing. Although little definitive data is available, preliminary studies indicate that hedgehog may be a powerful potential pharmacologic target to enhance bone formation. In this study, we will evaluate oral systemic agents that alter the activity of the hedgehog pathway. We will use a normal mouse femur fracture model and mice with an impaired ability to heal fractures. This approach is designed to provide a mechanistic analysis of hedgehog pathway modulation on fracture healing. If the proposed studies are successful, this would be a proof-of-concept that fracture healing can be upregulated or down-regulated by activation or inhibition of the hedgehog pathway, and would be grounds for further development of pharmacologic interventions that target the hedgehog pathway to enhance fracture healing. Several potential future strategies could then be employed. First, a more complete pathway analysis of the link between hedgehog activation and fracture could be performed. Some questions to be addressed include: Is this a direct effect on cells of the osteochondral lineage, or an indirect effect via increased angiogenesis, or both? At what stage of fracture healing is hedgehog most active? Next, a thorough exploration for other small molecules that activate the hedgehog pathway could be performed. Ideal dosing and safety profiles could be evaluated for Hh-Ag1.5 and other promising therapeutics. Overall, the proposed series of experiments could be an important first step in the development of a novel biological target for fracture healing stimulation.